Methods of treating acute stress disorder and posttraumatic stress disorder

Abstract

This invention relates to methods of treating posttraumatic stress disorder and acute stress disorder using pharmaceutical compositions comprising cyclobenzaprine, amitriptyline, or pharmaceutically acceptable salts thereof. In particular, it relates to methods of treating posttraumatic stress disorder or one or more symptoms thereof in a subject who has experienced a traumatic event less than or equal to about 9 years prior to the commencement or treatment. It also relates to methods of treating acute stress disorder or one or more symptoms thereof in a subject who has experienced a traumatic event less than or equal to about 1 month prior to the commencement of treatment.

1 . A method for treating post-traumatic stress disorder (PTSD) or one or more symptoms thereof in a subject in need thereof who has experienced a traumatic event less than or equal to about 9 years prior to the commencement of a treatment, wherein said treatment comprises administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof. 
     
     
         2 . A method for treating acute stress disorder (ASD) or one or more symptoms thereof in a subject in need thereof who has experienced a traumatic event less than or equal to 1 month prior to the commencement of a treatment, wherein said treatment comprises administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of cyclobenzaprine, amitriptyline, or a pharmaceutically acceptable salt thereof. 
     
     
         3 . The method of  claim 1  or  2 , wherein the traumatic event is a DSM-5 Criterion A traumatic event. 
     
     
         4 . The method of  claim 1  or  2 , wherein the pharmaceutical composition is administered once daily. 
     
     
         5 . The method of  claim 1  or  2 , wherein the treatment does not exceed 4 weeks. 
     
     
         6 . The method of  claim 2 , wherein the treatment of the ASD alleviates the development of PTSD and associated symptoms thereof in the subject. 
     
     
         7 . The method of  claim 1  or  2 , wherein cyclobenzaprine or amitriptyline is a free base. 
     
     
         8 . The method of  claim 1  or  2 , wherein the cyclobenzaprine or amitriptyline is a pharmaceutically acceptable salt thereof. 
     
     
         9 . The method of  claim 1  or  2 , wherein the pharmaceutical composition is formulated for sublingual, buccal, oral, suppository, intravenous, intramuscular, subcutaneous, inhalational, intranasal, transdermal, parenteral, rectal, or vaginal administration. 
     
     
         10 . The method of  claim 9 , wherein the pharmaceutical composition is formulated for sublingual administration. 
     
     
         11 . The method of  claim 1  or  2 , wherein the pharmaceutical composition comprises a basifying agent. 
     
     
         12 . The method of  claim 11 , wherein the basifying agent is selected from the group consisting of potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium carbonate, sodium bicarbonate, calcium carbonate, calcium bicarbonate, TRIS buffer, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, potassium carbonate, potassium bicarbonate, potassium acetate, sodium acetate, dipotassium citrate, tripotassium citrate, disodium citrate and trisodium citrate. 
     
     
         13 . The method of  claim 1  or  2 , wherein the efficacy of the treatment increases with decreasing time between experience of the traumatic event and the commencement of treatment. 
     
     
         14 . The method of  claim 1  or  2 , wherein the amount of the cyclobenzaprine, or a pharmaceutically acceptable salt thereof that is administered to the subject is between about 0.1 mg/day and about 50 mg/day. 
     
     
         15 . The method of  claim 14 , wherein the amount of the cyclobenzaprine or a pharmaceutically acceptable salt thereof that is administered to the subject is between about 0.5 mg/day and about 30 mg/day. 
     
     
         16 . The method of  claim 15 , where the amount of the cyclobenzaprine or pharmaceutically acceptable salt thereof that is administered to the subject is between about 1 mg/day and about 20 mg/day. 
     
     
         17 . The method of  claim 1  or  2 , wherein the amount of the amitriptyline, or a pharmaceutically acceptable salt thereof that is administered to the subject is between about 0.1 mg/day and about 150 mg/day. 
     
     
         18 . The method of  claim 17 , wherein the amount of amitriptyline or pharmaceutically acceptable salt thereof that is administered is between about 1.0 mg/day and about 90 mg/day. 
     
     
         19 . The method of  claim 18 , where the amount of the amitriptyline or a pharmaceutically acceptable salt thereof that is administered to the subject is between about 3 mg/day and about 60 mg/day. 
     
     
         20 . The method of  claim 1  or  2 , wherein the pharmaceutical composition is administered to the subject either sequentially or concurrently with a compound selected from the group consisting of an alpha-1-adrenergic receptor antagonist, a beta-adrenergic antagonist, an anticonvulsant, a selective serotonin reuptake inhibitor and a serotonin-norepinephrine reuptake inhibitor or a pharmaceutical composition containing one or more of them. 
     
     
         21 . The method of  claim 20 , wherein the alpha-1-adrenergic receptor antagonist is prazosin and wherein the selective serotonin reuptake inhibitor is sertraline, paroxetine, fluoxetine, citalopram or escitalopram. 
     
     
         22 . (canceled) 
     
     
         23 . The method of  claim 1  or  2 , wherein the treatment is combined with psychotherapeutic intervention. 
     
     
         24 . The method of  claim 1 , wherein at least one of the symptoms of PTSD is eliminated or ameliorated. 
     
     
         25 . The method of  claim 24 , wherein the symptoms of PTSD are selected from the group consisting of intrusion symptoms, avoidance symptoms, cognition and mood symptoms, arousal and reactivity symptoms, difficulty falling sleep, irritability, difficulty concentrating, hypervigilance, and persistent exaggerated startle response. 
     
     
         26 . The method of  claim 2 , wherein at least one of the symptoms of ASD is eliminated or ameliorated. 
     
     
         27 . The method of  claim 26 , wherein the symptoms of ASD are selected from the group consisting of reexperiencing symptoms, avoidance symptoms, arousal symptoms, difficulty with sleep, nightmares, irritability, difficulty concentrating, hypervigilance, persistent exaggerated startle response, feelings such as not knowing where you are, and feeling as if you are outside of your body. 
     
     
         28 . The method of  claim 1 , wherein the treatment is during the rapid recovery phase, the remitting phase, or the persistent phase of PTSD. 
     
     
         29 . A method for treating or preventing PTSD, ASD or one or more associated symptoms thereof in a subject in need or at risk thereof, wherein the method comprises:
 a) administering to the subject a pharmaceutical composition comprising cyclobenzaprine, amitriptyline or a pharmaceutically acceptable salt thereof;   b) assessing the efficacy of the method periodically over a course of the administration of the pharmaceutical composition;   c) suspending the administration of the pharmaceutical composition when the efficacy diminishes;   d) resuming the administration of the pharmaceutical composition 4 weeks after the administration was suspended;   wherein steps (a)-(d) may be repeated one or more times.   
     
     
         30 . A method for treating or preventing PTSD, ASD or one or more associated symptoms thereof in a subject in need or at risk thereof, wherein the method comprises:
 a) administering to the subject a pharmaceutical composition comprising cyclobenzaprine, amitriptyline or a pharmaceutically acceptable salt thereof;   b) suspending the administration of the pharmaceutical composition after about 4 weeks;   c) resuming the administration of the pharmaceutical composition about 4 weeks after suspending the administration;   wherein steps (a)-(c) may be repeated one or more times.   
     
     
         31 . The method of  claim 29  or  30 , wherein the treatment or prevention is of PTSD, and the subject has experienced a traumatic event less than or equal to about 9 years prior to the commencement of treatment. 
     
     
         32 . The method of  claim 29 , wherein the efficacy of is measured at least about every 2 weeks after the administration of the pharmaceutical composition begins. 
     
     
         33 . The method of  claim 32 , wherein the efficacy is assessed based on the subject's Clinician Administered PTSD Scale for DSM-5 (CAPS-5) score. 
     
     
         34 - 56 . (canceled) 
     
     
         57 . A method of determining a therapeutic dosage of cyclobenzaprine or a pharmaceutically acceptable salt thereof for the treatment or prevention of PTSD, ASD or one or more associated symptoms thereof in a subject in need or at risk thereof comprising:
 a) obtaining a suitable cell or tissue sample from a subject suffering from PTSD or ASD or at risk therefor;   b) identifying the CYP1A2, CYP2D6, and CYP3A4 genotype of said subject to determine if the patient has a high cyclobenzaprine metabolizer genotype;   c) assessing the subject's medical history for a history of smoking or use of medications that act as inducers of CYP3A4;   
       wherein if the subject has at least one of the criteria identified in step (b) or (c), the dose of cyclobenzaprine administered to the subject is greater than about 5 mg/day; 
       wherein if the subject does not have at least one of the criteria identified in step (b) or (c), the dose of cyclobenzaprine administered to the subject is about 5.6 mg/day or less. 
     
     
         58 . A method of determining a therapeutic dosage of amitriptyline or a pharmaceutically acceptable salt thereof for the treatment or prevention of PTSD, ASD or one or more associated symptoms thereof comprising:
 a) obtaining a suitable cell or tissue sample from a subject suffering from PTSD or ASD or at risk thereof;   b) identifying the CYP1A2, CYP2D6, and CYP3A4 genotype of said subject to determine if the patient has a high amitriptyline metabolizer genotype;   c) assessing the subject's medical history for a history of smoking or use of medications that act as inducers of CYP3A4;   
       wherein if the subject has at least one of the criteria identified in step (b) or (c), the dose of amitriptyline administered to the subject is greater than about 11 mg/day; 
       wherein if the subject does not have at least one of the criteria identified in step (b) or (c), the dose of amitriptyline administered to the subject is about 11.2 mg/day or less. 
     
     
         59 . The method of  claim 57  or  58 , wherein the medications that act as inducers of CYP3A4 are selected from carbamazepine, phenytoin, phenobarbital, and nevirapine. 
     
     
         60 . The method of  claim 57  or  58 , wherein the subject has experienced a traumatic event less than or equal to about 9 years prior to the commencement of treatment. 
     
     
         61 - 75 . (canceled)